2. Introduction to the HF problem
• Heart failure (HF) is a complex clinical
syndrome (not a single disease entity)
• Very common (#1 reason for hospitalization after age 65)
• The end result of virtually every type of heart
disease / heart problem
• Fundamental problem:
» Not enough output from the heart to the body and/or
» Pressures in the heart very high (fluid back-up)
• 2 types of HF: “preserved” vs. “reduced”
pumping function (ejection fraction [EF])
3. Introduction to the HF problem
• HF: end-result of almost every
cardiovascular disease
• There are many causes of heart failure:
» Ischemic heart disease (heart attacks)
» Hypertension (high blood pressure), diabetes
» Valve diseases (leaking or blocked up valves)
» Heart muscle diseases (genetic, drug-induced,
infections, toxins, or “idiopathic” [cause unknown])
» Congenital heart diseases, pericardial disease, heart
rhythm problems, and more…
4. Introduction to the HF problem
• HF has been variably defined as…
» A kidney problem: Na+ and fluid retention
» Forward failure vs backward failure
» Right-sided failure vs left-sided failure
» Systolic HF vs diastolic HF
» A neurohormonal problem
» An electromechanical problem
• The truth: most cases of HF are a
combination of several of these problems
5. Why is HF so important?
• HF: major medical problem
• #1 cause of hospitalization if age > 65y
» 1.1 million hospitalizations per year
• Prevalence ~7 million (2% of US population)
• Incidence > 550,000 new cases/year
• Costs more than all cancers combined
» $35 billion/year and rising
• Although many treatments exist, once
hospitalized for HF, prognosis is poor…
AHA Heart Disease and Stroke Statistics 2015 Update
6. Epidemiology of HF
Owan T et al. N Engl J Med 2006;355:251-259
• 5-year survival
after HF
hospitalization
• Only 30-35%
(dismal)
7. Epidemiology of HF
Yang H-X et al. Ann Thoracic Surg 2009.
T4 NSCLC
(Stage 3B or worse)
Owan T et al. N Engl J Med 2006;355:251-259
• Survival similar
to advanced
non-small cell
lung cancer…
8. The rising prevalence of HF…
• HTN, diabetes,
obesity epidemics
on the rise
• Better treatment
of heart attacks
• Effective but not
curative Rx for HF
• Aging population
Source: NHANES (1999-2004), CDC/NCHS and the American Heart Association
Prevalence of HF by age and gender
(United States: 1999-2004)
9. Heart failure staging system
ACC/AHA Heart Failure Practice Guidelines (HFpEF = HF with preserved EF; HFrEF = HF with reduced EF)
Stage A
High risk for
development of HF
HTN, CAD, DM
Stage B
Asymptomatic HF
(LV remodeling)
MI, LVH
Stage C
Symptomatic HF
HFpEF
HFrEF
Stage D
End-stage,
refractory HF
HFrEF
10. Heart failure staging system
ACC/AHA Heart Failure Practice Guidelines (HFpEF = HF with preserved EF; HFrEF = HF with reduced EF)
Stage A
High risk for
development of HF
HTN, CAD, DM
Stage B
Asymptomatic HF
(LV remodeling)
MI, LVH
Stage C
Symptomatic HF
HFpEF
HFrEF
Stage D
End-stage,
refractory HF
HFrEF
CURRENT FOCUS OF
DIAGNOSIS AND
TRAETMENT
FUTURE FOCUS OF DIAGNOSIS
AND TREATMENT
16. Key pathophysiology of HF#2: FP
• LV filling pressures:
» Pulmonary venous congestion
» Symptoms: shortness of breath, waking up
short of breath in middle of night
» Signs: pulmonary rales
• RV filling pressures:
» Systemic venous congestion
» Symptoms: leg swelling, abdominal bloating
» Signs: elevated neck veins, edema in legs
17. What causes filling pressures?
• Impaired LV or RV relaxation
• Reduced LV or RV compliance (stiffness
of the heart)
• Fluid overload (e.g., kidney failure)
19. HFpEF vs. HFrEF
HFpEF
Heart failure with
preserved ejection
fraction
“Diastolic HF”
HFrEF
Heart failure with
reduced ejection
fraction
“Systolic HF”
Left
ventricle
Left
ventricle
20. HFpEF vs. HFrEF
HFpEF
Heart failure with
preserved ejection
fraction
“Diastolic HF”
HFrEF
Heart failure with
reduced ejection
fraction
“Systolic HF”
Poorly understood
Increasing in prevalence
No definitive treatments
High morbidity/mortality
Well studied
Decreasing in prevalence
Many proven treatments
Decreasing morbidity
Decreasing mortality
21. HFpEF vs. HFrEF
HFpEF
Heart failure with
preserved ejection
fraction
“Diastolic HF”
HFrEF
Heart failure with
reduced ejection
fraction
“Systolic HF”
Poorly understood
Increasing in prevalence
No definitive treatments
High morbidity/mortality
Well studied
Decreasing in prevalence
Many proven treatments
Decreasing morbidity
Decreasing mortality
22. Systolic vs diastolic HF
• Traditional thinking…
» Systolic HF squeezing problem output
» Diastolic HF relaxation problem filling
pressures
• We now know that heart failure is more
complex:
» Systolic HF now called “HFrEF”
» Diastolic HF now called “HFpEF”
23. The bottom line…
HF is a syndrome
and
main differences between
systolic and diastolic HF
(HFrEF and HFpEF) =
anatomic structure and
function of heart muscle and
heart muscle cells
24. Differentiating types of HF
Characteristic HFpEF HFrEF
Clinical features
• Symptoms (e.g., dyspnea, orthopnea)
• Congestive state (e.g., edema)
• Neurohormonal activation (BNP, SNS, RAAS)
YES
YES
YES
YES
YES
YES
LV structure and function
• LV ejection fraction
• LV mass
• Relative wall thickness (i.e., mass/volume ratio)
• LV end-diastolic volume
• LV end-diastolic pressure, left atrial size
Normal
Normal
Exercise
• Exercise capacity
• Cardiac output augmentation
• End-diastolic pressure
25. Differentiating types of HF
Characteristic HFpEF HFrEF
Clinical features
• Symptoms (e.g., dyspnea, orthopnea)
• Congestive state (e.g., edema)
• Neurohormonal activation (BNP, SNS, RAAS)
YES
YES
YES
YES
YES
YES
LV structure and function
• LV ejection fraction
• LV mass
• Relative wall thickness (i.e., mass/volume ratio)
• LV end-diastolic volume
• LV end-diastolic pressure, left atrial size
Normal
Normal
Exercise
• Exercise capacity
• Cardiac output augmentation
• End-diastolic pressure
27. Sympathetic nervous system
• Cardiac output leads to decreased perfusion
pressure sensed by carotid baroreceptors
• Results in increased sympathetic outflow
• Initially a good thing:
» The body is trying to preserve BP
» Sympathetic nervous system = increases HR,
contractility, vasoconstriction
• But long term it’s a bad thing: heart
function gets worse
28. Natriuretic peptides (NPs)
• NPs are released into the
circulation when the
myocardium is under stress
• These hormones are
beneficial and counteract
the ill-effects of SNS, RAAS,
and AVP activation
• Elevated levels of BNP:
» Used to diagnose HF
» Associated with worse
outcomes
29. Why is neurohormonal activation bad?
• Natriuretic peptides are good
• Sympathetic nervous system, renin-angiotensin-
aldosterone system, vasopressin system: all bad
• Initially they are compensatory
• They very quickly worsen the HF syndrome
» Sodium and water retention: congestion
» Vasoconstriction: afterload = output
» Angiotensin II, aldosterone: cardiac fibrosis
(hardening of the heart tissue)
30. Overview of HF staging system
High Risk for Developing HF
Hypertension
CAD
Diabetes mellitus
Family history of cardiomyopathy
Asymptomatic HF
Previous MI
LV systolic dysfunction
Asymptomatic valvular disease
Symptomatic HF
Known structural heart disease
Shortness of breath and fatigue
Reduced exercise tolerance
Refractory
End-Stage HF
Marked symptoms at rest
despite maximal
medical therapy
A
B
C
D
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
31. Overview of HF treatment
• Goal #1:
» Prevent patients from ever getting
symptomatic (Stage C or D) HF
» Focus on Stage A and B HF for prevention
• Goal #2:
» Once symptomatic (Stage C) HF develops,
prevent hospitalization
• Goal #3:
» Prevent progression to Stage D HF
32. NYHA functional classification
• NYHA class I:
» No limitation
• NYHA class II:
» Slight limitation; dyspnea and
fatigue with moderate exertion
• NYHA class III:
» Marked limitation; dyspnea with
minimal activity
• NYHA class IV:
» Severe limitation; symptoms at rest
33. Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
New York Heart Association/Little Brown and Company, 1964.
Adapted from: Farrell MH et al. JAMA. 2002;287:890–897.
ACC/AHA HF Stage NYHA Functional Class
A At high risk for heart failure but without
structural heart disease or symptoms
of heart failure (eg, patients with
hypertension or coronary artery disease)
B Structural heart disease but without
symptoms of heart failure
C Structural heart disease with prior or
current symptoms of heart failure
D Refractory heart failure requiring
specialized interventions
I Asymptomatic
II Symptomatic with moderate exertion
IV Symptomatic at rest
III Symptomatic with minimal exertion
None
Classification of Severity
34. Mortality rate by NYHA class
The CONSENSUS Trial Study Group, N. Engl. J. Med., 1987
The SOLVD investigators, N. Engl. J. Med., 1991
The SOLVD investigators, N. Engl. J. Med., 1992
0
20
40
60
80
0 8 16 24 32 40 48
CONSENSUS
SOLVD-T
SOLVD-P
Class IV
Class II-III
Class I-II
35. Mortality rate by NYHA class
The CONSENSUS Trial Study Group, N. Engl. J. Med., 1987
The SOLVD investigators, N. Engl. J. Med., 1991
The SOLVD investigators, N. Engl. J. Med., 1992
0
20
40
60
80
0 8 16 24 32 40 48
CONSENSUS
SOLVD-T
SOLVD-P
Class IV
Class II-III
Class I-II
36. Symptoms are Important
Symptoms decrease quality of life and are
highly relevant to patients
Symptoms generally define the severity of
the disease
• Disease severity is one of the strongest
predictors of death in heart failure.
Symptoms often determine therapy
37. Health Status and Hospitalizations
Heidenreich, PA et al. JACC 2006; 47:752-6
39. Heart failure: unanswered questions
• Why do some people with risk factors
develop heart failure while others do not?
• How common is early heart failure (i.e.,
symptoms prior to hospitalization)?
• What is the best way to diagnose early
heart failure?
• What are the mechanisms behind early
heart failure?
40. Cohorts/ Trials/ Outcomes
studies investigating HF
• Have primarily focused on HF with
reduced ejection fraction (HFrEF),
• Or have not differentiated HF with
reduced vs. preserved EF
• Diagnosis of HF based on
hospitalizations, primarily
• The diagnosis of early heart failure is
missing in these studies
41. CLINICAL, SYMPTOMATIC HF IS A SPECTRUM
Depends on: (1) type of clinical presentation; (2) MD
threshold to hospitalize the patient vs. outpatient treatment
OUTPATIENT
Dyspnea on
exertion due to
myocardial problem
with evidence of
CO and/or
PCWP at rest or
with exertion
CLINICAL SPECTRUM
Heart failure may have insidious onset, characterized by
poor exercise capacity, dyspnea/ pulmonary signs, but
not recognized until severe/ decompensated
INPATIENT
CHF
hospitalization due
to overt volume
overload and/or low
output state
Traditional HF endpoint
in epidemiology studies
42. Stage A
High risk for
development of HF
(HTN, CAD, DM,
obesity, CKD, etc) Stage B
Asymptomatic HF
(abnormal cardiac
structure/function)
Stage C
Symptomatic HF
Stage D
End-stage,
refractory HF
HF Stages
Modified from Hunt et al, ACC/AHA Guidelines for the Evaluation and Management of
Chronic Heart Failure in the Adult. 2005
Most elderly are
at risk (Stage A)
and many are in
Stage B HF
Stage BC: Critical
transition point but
poorly understood. What
defines the development
of symptomatic HF?
★
43. ENVIRONMENT, DIET COMORBIDITIES GENETIC SUSCEPTIBILITY
VULNERABLE HEART,
VULNERABLE PATIENT
HFpEF
EXERCISE
INTOLERANCE
HFpEF
(Early HF)
VOLUME
OVERLOAD
HFpEF
PULMONARY HTN,
RV FAILURE
HFpEF
Types of HFpEF
Shah SJ. JACC 2013
By 2020, 65% of hospitalized HF will have EF>40%
44. Framingham Criteria for HF
• Diagnosis requires the simultaneous
presence of at least 2 major criteria or 1
major criterion and 2 minor criteria
• Minor criteria are acceptable only if they can
not be attributed to another medical
condition (i.e. pulmonary hypertension,
chronic lung, liver, or kidney diseases)
45. Major/Minor Framingham Criteria
• Paroxysmal nocturnal dyspnea
• Neck vein distention; Rales (lung sounds); S3 gallop
• Incr heart size on chest Xray; Acute Pulm Edema
• Increased central venous pressure
• Hepatojugular reflux
• Weight loss >4.5 kg in 5 days in response to Rx
• Bilateral ankle edema
• Dyspnea on ordinary exertion; nocturnal cough
• Hepatomegaly; Pleural effusion
• Decrease in vital capacity by one third from maximum recorded
• Tachycardia (heart rate>120 beats/min)
46. Other Schemes for defining HF
• Several Other Formulations
– Gothenberg
– NHANES
– Boston
• All these criteria predate the
availability of biomarkers or the
inclusion of structural assessments
• Different “definitions” influence
epidemiology!
47. Transthoracic Echocardiography
(heart ultrasound)
• Provides measures of heart structure
and function
– Left ventricular ejection fraction (squeezing
function)
– Chamber size (is the heart enlarged?)
– LV wall thickness (hypertrophy)
– Measures of chamber relaxation (diastology)
– Valvular anatomy and function
• Advantages
– Real time, Non-invasive, No radiation
– Relatively “inexpensive”
• Disadvantages
– Not as precise as MRI for some measures
48. Brain Natriuretic Peptides
• Secreted as proBNP by heart cells,
cleaved into BNP and NTproBNP
– In response to atrial/ventricular stretch
– BNP is active component, signals to kidney
to produce diuresis
• Shown to be markedly elevated in acute
HF, can differentiate between cardiac
and non cardiac causes of dyspnea
– Also elevated by renal failure
• Within “normal” ranges, higher levels
are predictive of future risk of HF
49. Transition from Risk Factors to
Heart Failure: Prevalence,
Pathogenesis, and Phenomics
Co-PIs: Alain Bertoni MD MPH and Sanjiv Shah MD
Other key personnel:
C Rodriquez, J Yeboah, S Rosas, H Chen, A Folsom, S Shea, K Watson,
W Post, K Liu, R Kronmal, R Tracy, B Freed, R Deo, and J Chirinos
50. Dyspnea and/or exercise intolerance due to
underlying cardiac problem
No or minimal overt volume overload
Majority have a normal or near-normal LVEF
May have a normal BNP
Elevated LV filling pressure at rest or with
volume loading, hand-grip, or exercise
What is early HF?
Borlaug BA, et al. Circ Heart Fail 2010
Penicka M, et al. JACC 2010
Shah SJ. JACC 2013
51. 28% of MESA ppt’s reported pedal edema at baseline
Pedal edema not associated with LV or RV systolic
dysfunction on cardiac MRI
Pedal edema was associated with:
• Orthopnea (OR 1.66 [95% CI 1.30-2.12])
• PND (OR 1.95 [95% CI 1.21-2.68])
• Elevated NTproBNP (OR 1.80 [95% CI 1.21-2.68])
• Incident HF (adj. HR 1.43 [95% CI 1.02-1.99])
How common is early HF in MESA?
Yeboah J, et al. (unpublished data)
52. To determine the prevalence/subtype of early
HF by assessing functional status (6MWT),
physical activity (survey), symptoms,
NTproBNP, echocardiography, arterial
stiffness measures, and in a Wake Forest sub-
sample, cardiopulmonary exercise testing.
AIM 1
Prevalence of early HF
53. To measure key physiologic parameters, risk
factors, and novel biomarkers (ST2, gal-3, FGF23)
concurrent to the assessment of HF status, and
use the data from prior MESA exams to examine
the associations between ideal CV health, risk
factors, biomarkers, and changes in risk factors
with all HF and early HFpEF specifically
AIM 2
Pathogenesis of early HF
54. To perform phenomics (machine learning
analysis) of previously ascertained quantitative
MESA data to define differential phenotype
signatures (pheno-groups) and relate these
pheno-groups to cardiac structure/function at
Y15 and the prevalence and type of HF (e.g.,
early or overt HFpEF or HFrEF)
AIM 3
Phenomics of early HF
55. HEART FAILURE
RISK FACTOR
COMBINATIONS
HEART FAILURE
PATHOPHYSIOLOGIC
SUBTYPES
HYPOTHESIS: Specific HF risk factor phenotypic
signatures are associated with specific
HF pathophysiologic subtypes
Shah SJ, et al. Heart Fail Clin 2014
57. All participants (N=3500) will undergo
contract exam, PLUS
6-minute walk test
Kansas City Cardiomyopathy Questionnaire (KCCQ12)
Dyspnea Questionnaire (MESA Lung)
Physical Activity Survey (MESA TWPAS)
METHODS (1)
58. Laboratory Testing
All: Serum NTproBNP, glucose, creatinine, urine
microalbumin
Case-cohort approach: novel biomarkers (ST2,
galectin-3, FGF23) to be performed after exam 6
Budgeted to run 1000 assays for each biomarker
METHODS (2)
59. Echocardiography with Doppler, tissue Doppler
and speckle-tracking
At rest
Passive leg raise (preload)
Arterial stiffness (Fukuda VaSera)
Cardiopulmonary exercise testing in a subset
(n=300) to validate early HF dx, as CPEX is gold
standard for evaluating exercise intolerance
METHODS (3)
61. Definition of early HF:
No prior HF hospitalization and
Presence of HF symptoms or functional
limitation suggestive of HF and
NTproBNP or echo evidence of elevated LV
filling pressure (at rest or with passive leg
raise or bilateral cuff occlusion)
METHODS (4)
63. Clinical impact within the next 5 years:
Characterization of the early HF syndrome,
including prevalence data, diagnostic criteria,
and clinical characteristics will help inform
design of prevention and intervention trials
Identification of patients at highest risk for
transitioning from Stage BC (early) HF
IMPACT
![Introduction to the HF problem
• Heart failure (HF) is a complex clinical
syndrome (not a single disease entity)
• Very common (#1 reason for hospitalization after age 65)
• The end result of virtually every type of heart
disease / heart problem
• Fundamental problem:
» Not enough output from the heart to the body and/or
» Pressures in the heart very high (fluid back-up)
• 2 types of HF: “preserved” vs. “reduced”
pumping function (ejection fraction [EF])](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)